The field of the invention is pharmaceutical drug screening. Pharmaceutical research and development is a multibillion dollar industry. Much of these resources are consumed in efforts to focus the specificity of lead compounds. In addition, many programs are aborted after decades of costly yet fruitless efforts to limit side effects or toxicity of candidate drugs. Accordingly, tools that can abbreviate the research and discovery phase of drug development are desirable. Several in vitro or cell culture-based methods have been described for identifying compounds with a particular biological effect through the activation of a linked reporter. Gadski et al. (1992) EP 92304902.7 describes methods for identifying substances which regulate the synthesis of an apolipoprotein; Evans et al. (1991) U.S. Pat. No. 4,981,784 describes methods for identifying ligand for a receptor and Farr et al. (1994) WO 94/17208 describes methods and kits utilizing stress promoters to determine toxicity of a compound.
In general, the principle that has been applied in the existing pharmaceutical industry for the discovery and development of new lead compounds for drugs has been the establishment of sensitive and reliable in vitro assays for purified enzymes, and then screening large numbers of compounds and culture supernatants for any ability to inhibit enzyme activity. The present invention exploits the recent advances in genome science to provide for the rapid screening of large numbers of compounds against a systemic target comprising substantially all targets in a pathway, organism, etc. for rare compounds having the ability to inhibit the protein of interest. The invention described herein, in effect, turns the drug discovery process inside out. This invention provides information on the mechanism of action of every compound that affects cells, regardless of the target. In addition, the relative specificity of all lead compounds is immediately established.